Schizophrenia is a major mental disorder that affects approximately 1% of the population worldwide. Although many patients respond well to currently available medications, including both typical and atypical antipsychotics, the majority of patient shows significant residual symptoms despite best available treatment. Persistent negative and cognitive symptoms are particularly associated with poor outcome in schizophrenia. All current medications for schizophrenia, including both typical and atypical antipsychotics, bind primarily to dopamine (D2) receptors. The goal of the present study is to develop an adjunctive treatment strategy for schizophrenia based upon the PCP/NMDA model. Phencyclidine (PCP) induces psychotic symptoms in schizophrenia by blocking neurotransmission at N-methyI-D-aspartate (NMDA)-type glutamate receptors. Behavioral effects of PCP in rodents are reversed by the amino acids glycine and D-serine, which bind to the glycine modulatory site of the NMDA receptor complex. In schizophrenia, both glycine and D-serine have been shown to ameliorate persistent negative and cognitive symptoms of the disorder. The goal of the present study is to develop glycine and D-serine as commercializable treatments for schizophrenia. Glycine must be administered at relatively high dose (60 g/d) to significantly elevate brain glycine levels. In the case of glycine, therefore, the goal of the present project is to develop a palatable, unit dose formulation that can be administered in routine clinical practice. D-serine is effective at doses of approximately 2 g/d. However, D-serine has been shown to be nephrotoxic in rats (but not other species). In order for D-serine to be approved for use in the US, therefore, formal preclinical toxicity studies must be performed. Funds are therefore requested to conduct preclinical toxicology studies, followed by a double blind, placebo-controlled study. The overall goal of these projects is to develop new treatments for persistent negative and cognitive symptoms of schizophrenia. Development of D-serine and/or glycine will be conducted under FDA supervision, and will conform to all required FDA policies and procedures.